We have developed a model of sexually transmitted AIDS using vaginal infection of female rhesus macaques with simian immunodeficiency virus (SIV) for studies of pathogenesis and evaluation of vaccines. We have shown that intravaginal inoculation of adult female rhesus macaques with a pathogenic, uncloned SIVmac isolate containing a mixture of virus genotypes consistently results in infection. However, as the inoculum titer is reduced, virus load after intravaginal challenge is lower and may be transient. This observation in macaques is relevant because women are often exposed to relatively low doses of HIV by sexual contact. It is possible that mucosal surfaces may restrict vaginal transmission of some viral variants and so alter virus levels or disease course in HIV-infected women. We tested the hypothesis that virus load in peripheral blood of macaques after intravaginal SIV inoculation depends on viral genotype. We tested viruses from two, pathogenic molecular clones of SIV that produce persistent infection after intravenous inoculation. Two adult female rhesus macaques were inoculated intravaginally with 100,000 tissue culture infectious doses (TCID 50%) SIVmac239 and four females were inoculated intravaginally with 100,000 TCID 50% of a recombinant SIV constructed from SIVmac239 and the non-pathogenic molecular clone, SIVmac1A11. The levels of viremia following infection with each SIV variant were distinct and mirror the pattern observed after intravenous inoculation SIVmac239 induces a 10- to 100-fold higher level of virus-infected cells in peripheral blood than does the recombinant virus. These results show that intravaginal inoculation with SIV variants consistently produces infection and that virus-specific factors, but not the route of virus exposure, account for the differences in virus load after infection observed for these SIV variants in adult female rhesus macaques. *KEY* HIV sexual transmission, AIDS, SIV variants, Vaginal inoculation